Dissertations / Theses on the topic 'Apnea'

Obstructive Sleep Apnea Syndrome (OSAS) is defined as a sleep related breathing disorder that causes the body to stop breathing for about 10 seconds and mostly ends with a loud sound due to the opening of the airway. OSAS is traditionally diagnosed using polysomnography, which requires a whole night stay at the sleep laboratory of a hospital, with multiple electrodes attached to the patient'
s body. Snoring is a symptom which may indicate presence of OSAS
thus investigation of snoring sounds, which can be recorded in the patient'
s own sleeping environment, has become popular in recent years to diagnose OSAS. In this study, we aim to develop a new method to detect post-apnea snoring episodes with the goal of diagnosing apnea or creating a new criteria similar to apnea / hypopnea index. In this method, first segmentation is done to eliminate the silence parts and only deal with active. Then these episodes are represented by distinctive features
some of these features are available in literature but some of them are novel. Finally, these episodes are classified using supervised and unsupervised methods. We are especially interested in detecting post apnea episodes, hence the apnea periods. False alarm rates are reduced by adding additional constraints into the detection algorithm. These methods are applied to snoring sound signals of OSAS patients, recorded in Gulhane Military Medical Academy, to verify the success of our algorithms.

Background: Obstructive sleep apnea (OSA) is a sleep disorder characterized by episodes of cessation of breathing (apnea) during sleep. Unfortunately, a significant number of surgical patients are unaware they are afflicted with this disorder increasing the risks of postoperative complications. The lingering effect of general anesthesia causes an increase in frequency of airway collapse, leading to longer periods of apnea. This increasingly common sleep disorder is concerning for many anesthesia providers. Purpose: The purpose of this study was to evaluate the anesthesia provider's knowledge and postoperative management of patients with suspected or diagnosed OSA. Setting: The study setting was a local urban hospital Mountain Vista Medical Center (MVMC) in Gilbert, AZ. The study included (N=7) participants, who were predominantly male (85%) and a majority of the participants were Master’s prepared (85%) anesthesia providers. Method: An online survey was disseminated to participants via email. The survey included questions regarding the anesthesia provider's knowledge and postoperative practice habits of patients with suspected or diagnosed OSA at MVMC. Results: The response rate was (24%). All the respondents acknowledged that OSA was a risk factor for postoperative complications. Over half of the respondents (85%) reported encountering postoperative complications such as desaturation and apnea in their patients with OSA. The main complication that was encountered was postoperative apnea (50%), followed by decreased in saturations (33.33%), and one respondent (16.67%) encountered re-intubation during the postoperative period. However, the most important finding of the study is that over half of the providers did not routinely include continued positive airway pressure (CPAP)/noninvasive positive pressure ventilation (NIPPV) in their postoperative management of patients with suspected or known OSA due to the time needed to initiate the therapy. Conclusion: The study illustrates that a majority of anesthesia providers at MVMC agreed OSA is a significant risk factor for postoperative complications, but time constraints limited the implementation of noninvasive ventilation (NIV) therapies. Recommended strategies would be to establish a task force to examine this barrier to therapy and develop plans to address it.

The overall aim of this thesis was to understand gender differences in obstructive sleep apnea (OSA) and use this information to develop a tailored therapy for female patients. Specific aims were to determine whether gender differences commonly reported in the literature are present in mild OSA and upper airway resistance syndrome (UARS) patient groups, and whether symptoms could be linked to respiratory parameters in these groups. The final aim was to develop, test and validate a new AutoSet treatment for female OSA patients. CHAPTER 1 of this thesis provides a detailed review of gender differences in the prevalence, symptoms, clinical experience, and health outcomes of OSA and UARS patients, with a focus on the implications of different scoring rules. CHAPTER 2 reviews of quality of life questionnaires from 259 untreated patients with mild OSA. Females reported statistically significantly higher levels of sleepiness, fatigue, insomnia, and anxiety/depression compared to males. CHAPTER 3 of this thesis reviews polygraphy data from patients with mild OSA. Male patients were found to have significantly more breathing disturbances than females, however many of these difference disappeared when updated scoring criteria were used. Some weak correlations were found between respiratory parameters and symptoms; however, no clear conclusions could be drawn. CHAPTER 4 outlines the development of a new AutoSet device designed for female- specific breathing patterns. The remaining chapters (CHAPTER 5, and CHAPTER 6) of this thesis describe the testing and validation activities undertaken on the AutoSet F, including a clinical trial to test efficacy; a bench test to compare performance against other commercially available devices; a controlled product launch to validate the features of the algorithm; and finally a clinical trial which demonstrated improvements in sleep efficacy and quality of life over a three-month usage period. In summary, this thesis has shown that at the mild end of the OSA spectrum females are more symptomatic than males, even though respiratory differences in the genders are less pronounced than those described in moderate-to-severe patients. An AutoSet designed specifically for female OSA patients was successful in demonstrating efficacy and clinical effectiveness.

Introdução: A utilidade de questionários para o diagnóstico de apneia obstrutiva do sono está bem estabelecida em adultos, mas permanece indefinida em idosos. Objetivo: Avaliar as propriedades preditivas dos questionários mais comumente empregados na população em geral em idosos fisicamente independentes. Desenho: Transversal. Local: Unidade de cuidados primários de saúde pública filiada a hospital universitário. Participantes: Roncadores fisicamente independentes com idade entre 65 a 80 anos cadastrados em um hospital universitário foram abordados por telefone e convidados a participar. Métodos: Os participantes foram submetidos à polissonografia portátil. Sensibilidade, especificidade, razão de verossimilhança positiva e negativa, área sob a curva ROC e psicometria clássica foram utilizados para avaliar a precisão e a medição de propriedades diagnósticas de três instrumentos validados para uso na população geral, sendo incerta sua utilização em idosos. Resultados: A amostra de 131 idosos fisicamente independentes, 50% homens, 58% aposentados, foram incluídos. Epworth>6 apresentou uma precisão de 61% para identificar IAH≥15. Epworth>10, ponto de corte usualmente empregado em adultos, apresentou pior desempenho diagnóstico. Sexo masculino e ser aposentado tiveram menor probabilidade de estarem associados com apneia obstrutiva do sono grave. Para prever IAH≥15, a área sob a curva ROC para Epworth>6 foi significativa, mas não para STOP-bang>2 e Atenas>5. Na regressão logística para prever IAH≥15, controlando para diversos fatores, apenas Epworth>6 e Atenas>5 permaneceram significativas no modelo. Conclusão: Em idosos independentes, uma escala de sonolência de Epworth com ponto de corte de 6 tem melhor desempenho diagnóstico do que questionários comumente empregados para prever um IAH≥15.
Background: The usefulness of questionnaires for diagnosis of sleep apnea is well established in adults, but remains undefined in the elderly population. Objective: To evaluate the predictive properties of the most commonly employed questionnaires in physically independent elderly people from the general population. Design: Cross-sectional. Setting: Public health primary care unit affiliated to university hospital. Participants: Physically independent snorers aged 65 to 80 years adscript to a university hospital were approached by telephone and invited to participate. Measurements: Participants underwent portable polysomnography. Sensitivity, specificity, positive and negative likelihood ratios, area under the ROC curve, and classical psychometrics were used to assess diagnostic accuracy and measurement properties of three validated instruments for use in the general population, making their usability in elderly populations uncertain. Results: A sample of 131 independently-living elderly people, 50% male, 58% retired, was included. For identifying AHI≥15, an Epworth>6 had an accuracy of 61%. Epworth>10, the usually employed cut-off point in adults, had poorer diagnostic performance. Male gender and retirement were protective of more severe OSA. For predicting AHI≥15, the area under the ROC curve for Epworth>6 was significant, but not for STOP-Bang>2 and Athens>5. In logistic regression to predict AHI≥15, after controlling for several confounders, Epworth>6, and Athens>5 were the only variables that remained significant in the model. Conclusion: In independent elderly, an Epworth sleepiness scale cut-point of 6 has better diagnostic performance than commonly employed questionnaires to predict an AHI≥15.

Introduction: Obstructive sleep apnea (OSA) is a common chronic disorder consisting of episodes with impaired breathing due to obstruction of the upper airways. Treatment with Continuous Positive Airway Pressure (CPAP) is a potentially effective treatment, but adherence is low. Several potential factors affecting adherence, e.g., subjective sleepiness and personality, are only quantifiable through questionnaires. Better knowledge about psychometric properties of such questionnaires might improve future research on CPAP adherence and thus lead to better treatment options. Aim: Study I: To describe the devlopment and initial testing of the Side Effects of CPAP treatment Inventory (SECI) questionnaire. Study II: To describe the prevalence of Type D personality in OSAS patients with CPAP treatment longer than 6 months and the association with self-reported side effects and adherence. Study III: To study whether any of the items in the Epworth Sleepiness Scale (ESS) exhibit differential item functioning and, if so, to which degree. Study IV: To examine the evolution of CPAP side effects over time; and prospectively assess correlations between early CPAP side effects and treatment adherence. Patients and Methods: In study I, SECI items were based on a literature review, an expert panel and interviews with patients. It was then mailed to 329 CPAP-treated OSAS patients. Based on this, a principal component analysis was performed, and SECI results were compared between adherent and non-adherent patients. In study II, the population consisted of 247 OSAS patients with ongoing CPAP treatment. The DS14 was used to assess the prevalence of type D personality, and SECI and adherence data from medical records were used to correlate Type D personality to side effects and adherence. In study III, the population consisted of pooled data from 1,167 subjects who had completed the ESS in five other studies. Ordinal regression and Rasch analysis were used to assess the existence of differential item functioning for age and gender. The cutoff for age was 65 years in the Rasch analysis. In study IV, SECI was sent to 186 subjects with newly diagnosed OSAS three times during the first year on CPAP. SECI results were followed over time within subjects, and were correlated to treatment dropout during the first year and machine usage time after 6 months. Results: SECI provides a valid and reliable instrument to measure side effects, and non-adherent patients have higher scores (i.e., were more bothered by side effects) than adherent patients (study I). Type D personality was prevalent in approximately 30 % of CPAP treated OSAS patients, and was associated to poorer objective and subjective adherence as well as more side effects (study II). Differential item functioning was present in items 3, 4 and 8 for age in both DIF analyses, and to gender in item 8 the Rasch analysis (study III). Dry mouth and increased number of awakenings were consistently associated to poorer adherence in CPAP treated patients. Side effects both emerged and resolved over time (study IV). Conclusions: Differences in previous research regarding side effects and CPAP adherence might be explained by differences in how side effects and adherence are defined. While some side effects are related to adherence, others are not. Side effects are furthermore not stable over time, and might be related to personality. ESS scores are also related to CPAP adherence according to previous research, but might be affected by other factors than sleepiness, such as age and possibly gender.

Introduction Acromegaly is an endocrine disorder characterized by excessive growth hormone production.The most common cause is a benign pituitary adenoma, which can be an isolated tumor or part of a group of concomitant endocrine neoplasms. We present a case of a middle aged woman with sleep apnea and a newly diagnosed acromegaly secondary to a pituitary macroadenoma. Case presentation A 51-year-old woman was seen in the endocrinology clinic for evaluation of hyperparathyroidism and mild hypercalcemia. She had no symptoms related to hypercalcemia. However, she complained of enlargement of her fingers and toes. She also reported galactorrhea and breast engorgement. There was no hyperhidrosis or frontal bossing present and she denied headaches or vision symptoms. Past medical history was significant for obstructive sleep apnea. Insulin like growth factor level was 630 ng/ml (reference 53 - 190 ng/ml), prolactin level was 109 ng/ml (reference 1.9- 25 ng/ml), and Follicular stimulating hormone was 0.4mIU/ml (reference 1.2 - 21.0 mIU/ml). TSH, free T4, ACTH, and cortisol were normal. The labs were consistent with pituitary macroadenoma secreting growth hormone (GH) and prolactin. MRI pituitary showed a 1.9 cm macroadenoma with no evidence of optic nerve compression. Due to the coexisting diagnoses of hyperparathyroidism and pituitary adenoma, CT abdomen was done to evaluate for neuroendocrine tumor and to rule out Multiple Endocrine Neoplasia (MEN) Type 1. She then underwent transsphenoidal resection of the pituitary, with immunostaining reflecting diffuse prolactin and patchy GH expression. Post-surgery IGF, prolactin, thyroid function tests were normal. She was started on hydrocortisone replacement due to abnormal ACTH and cortisol. Her calcium levels normalized, and further genetic testing for MEN was abandoned. Her repeat sleep study also showed resolution of sleep apnea. She did not suffer from further symptoms of acromegaly and was scheduled for periodic surveillance for thyroid axis dysfunction. Discussion Dysregulated growth hormone production seen in acromegaly leads to increased GH and IGF-1 levels. It has many ramifications including debilitating arthritis from osteoarthropathy, glucose intolerance due to insulin resistance, higher propensity for GI neoplasms, and macroglossia with prognathism causing sleep apnea. Average lifespan is decreased by 30% due to cardiovascular and pulmonary dysfunction. Treatment is aimed at decreasing IGF levels and controlling any mass effect or metabolic abnormalities caused by the tumor. Treatment options include invasive procedures for good surgical candidates and medical therapy via somatostatin analogue for patients who are not. Residual or unresectable tumors can be treated with medical therapy or radiation therapy if there is no response to medication.

The focus of this thesis was to capture and measure carbon dioxide concentrations upon exhalation to determine if an apnea event is occurring. Research in the fields of respiratory physiology and apnea built the foundation for the design of the standoff infant apnea monitor. The monitor is designed to track infant respiration using carbon dioxide and sound signatures of breath without touching the infant. Each detection system, audio and carbon dioxide, were designed separately and brought together for a final proof-of-concept device. The software was developed using LabView and run on a Netbook. Testing was conducted on healthy adults to fine tune the carbon dioxide sensor and measure its response during simulated apnea events. Overnight testing showed that the combined system detected fewer false alarms than either system alone. Infant testing was conducted to determine if the proof-of-concept standoff monitor could detect infant breath at specified distance. The results showed that both detection systems can detect infant breath consistently at distances less than one foot from the infant and poorly at distances exceeding one foot. Finally, conclusions were drawn and interpreted to aid in the design of future generations of the standoff infant apnea monitor. Other research avenues where this technology may be useful were also discussed.

Objective: To document the existence of a relationship between apnea of prematurity (AOP) and gastroesophageal reflux (GER) in preterm infants. Setting: One Neonatal Intensive Care Unit Patients: Twenty-six preterm infants (gestational age<32 weeks) with recurrent apneas. Intervention: Simultaneous and synchronized recording of polysomnography and pH-impedance monitoring (pH-MII). Polysomnography detects and characterizes apneas, by recording of breathing movement, nasal airflow, electrocardiogram, pulse oximeter saturation. pH-MII is the state-of-theart methodology for GER detection in preterm newborns. Main outcome measures: Relationship between AOP and GER, which were considered temporally related if both started within 30 seconds of each other. Results: One-hundred-fifty-four apneas out of 1136 were temporally related to GER. The frequency of apnea during the one-minute time around the onset of GER was significantly higher than the one detected in the GER-free period (p=0.03). Furthermore, the frequency of apnea in the 30 seconds after GER (GER-triggered apneas) was greater than that detected in the 30 seconds before (p=0.01). A great inter-individual variability was documented in the proportion of GERtriggered apneas. A strong correlation between total number of apneas and the difference between apneas detected 30 seconds after and before GER was found (p=0.034). Conclusions: Our data show that a variable rate of apneas can be triggered by GER in very preterm infant. Further studies are needed to recognise clinical features which identify those patients who are more susceptible to GER-triggered apneas.

Objective: To document the existence of a relationship between apnea of prematurity (AOP) and gastroesophageal reflux (GER) in preterm infants. Setting: One Neonatal Intensive Care Unit Patients: Twenty-six preterm infants (gestational age<32 weeks) with recurrent apneas. Intervention: Simultaneous and synchronized recording of polysomnography and pH-impedance monitoring (pH-MII). Polysomnography detects and characterizes apneas, by recording of breathing movement, nasal airflow, electrocardiogram, pulse oximeter saturation. pH-MII is the state-of-theart methodology for GER detection in preterm newborns. Main outcome measures: Relationship between AOP and GER, which were considered temporally related if both started within 30 seconds of each other. Results: One-hundred-fifty-four apneas out of 1136 were temporally related to GER. The frequency of apnea during the one-minute time around the onset of GER was significantly higher than the one detected in the GER-free period (p=0.03). Furthermore, the frequency of apnea in the 30 seconds after GER (GER-triggered apneas) was greater than that detected in the 30 seconds before (p=0.01). A great inter-individual variability was documented in the proportion of GERtriggered apneas. A strong correlation between total number of apneas and the difference between apneas detected 30 seconds after and before GER was found (p=0.034). Conclusions: Our data show that a variable rate of apneas can be triggered by GER in very preterm infant. Further studies are needed to recognise clinical features which identify those patients who are more susceptible to GER-triggered apneas.

Un terzo della popolazione europea è affetta da apnee ostruttive del sonno (OSA), patologia che ha conseguenze negative su morbilità cardiovascolare e qualità della vita. L’OSA è caratterizzata da ripetuti episodi di collasso delle alte vie respiratorie che determinano ipossia intermittente, modifiche della pressione intratoracica e risvegli corticali. L’ipossia intermittente ha un ruolo chiave nel determinare le conseguenze cardiovascolari dei disturbi del respiro nel sonno e può sovrapporsi, peggiorandone la prognosi, a condizioni caratterizzate da ipossia tonica quali l’alta quota o le patologie respiratorie croniche o infettive, esacerbando lo stress ossidativo, l’angiogenesi e quindi l’attivazione del sistema nervoso simpatico con conseguenti incrementi della pressione arteriosa, della frequenza cardiaca e dell’infiammazione. Il trattamento gold standard per l’OSA è la terapia ventilatoria che risulta però non tollerata dalla metà dei pazienti che ne fanno uso. Nuove strategie terapeutiche sono pertanto auspicabili. Recentemente sono stati identificati specifici fattori fisiopatologici che contribuiscono allo sviluppo dell’OSA: un’elevata collassabilità delle vie aeree superiori, l’instabilità del sistema di controllo del respiro, una ridotta soglia di arousal ed una ridotta risposta compensatoria dei muscoli dilatatori della faringe. Quest’ultima è dovuta alla perdita di attività noradrenergica e aumento delle influenze muscariniche alle alte vie aeree. Il riconoscimento di questi tratti fisiopatologici ha permesso di ipotizzare e sviluppare nuove strategie terapeutiche per l’OSA. Obiettivo: Valutare l’efficacia della somministrazione per 1 settimana della combinazione di reboxetina (noradrenergico) ed ossibutinina (antimuscarinico) sul trattamento dell’OSA e dell’effetto dei farmaci sugli endotipi fisiopatologici. Metodi: E’ stato condotto uno studio randomizzato controllato cross-over in doppio cieco per comparare 4mg di reboxetina più 5mg di ossibutinina (reb-oxy) in pazienti con OSA. I pazienti sono stati sottoposti ad una polisonnografia basale (PSG), una dopo 7 notti di assunzione di reb-oxy ed una dopo 7 notti di assunzione di placebo per confrontare l’indice di apnea-ipopnea (AHI–outcome primario). Outcome secondari comprendevano il carico ipossico, modifiche degli endotipi, la variabilità della frequenza cardiaca, test di vigilanza. Risultati: Hanno completato lo studio 16 pazienti con età 57 [51-61] anni (mediana [range interquartilico]) ed indice di massa corporea 30 [26-36] kg/m2. Reb-oxy ha determinato una riduzione di AHI da 49 [35-57] eventi/h al basale a 18 [13-21] eventi/h (59% di riduzione mediana) e 39 [29-48] eventi/h (6% riduzione mediana) confrontato con il placebo (p<0·001). La frequenza cardiaca mediana durante la PSG è stata 65 [60-69] bpm al basale ed è aumentata fino a 69 [64-77] bpm dopo reb-oxy e 66 [59-70] bpm dopo placebo (p=0.02). La somministrazione di reb-oxy non ha comportato modifiche di variabilità della frequenza cardiaca, pressione arteriosa nelle 24 ore. Il test di vigilanza si è ridotto da 250 [239-312] ms al basale a 223 [172-244] ms dopo reb-oxy versus 264 [217-284] ms dopo placebo (p<0·001). Conclusioni: Il miglioramento delle conoscenze della fisiopatologia dell’OSA ha permesso di identificare la responsività muscolare delle alte vie come target principale di strategia terapeutica per l’OSA, predisponendo il percorso verso la medicina di precisione anche nel contesto dei disturbi del respiro nel sonno. Il nostro studio ha evidenziato il dato pionieristico dell’effetto positivo della somministrazione di reboxetina più ossibutinina sulla gravità dell’OSA e sull’ipossia associata agli eventi ostruttivi nel sonno. I risultati del nostro studio sottolineano la possibilità di una terapia personalizzata con farmaci per trattare l’OSA ed il carico ipossico ad essa relato.
Introduction: Obstructive sleep apnea (OSA) affects one third of the population in Europe and has major negative consequences for cardiovascular disease and quality of life. OSA is characterized by recurrent episodes of apneas and hypopneas associated with repetitive episodes of intermittent hypoxemia, intrathoracic pressure changes, and arousals. Intermittent hypoxemia, particularly with concomitant hypercapnia, activates the sympathetic nervous system and it is the major contributor to negative cardiovascular consequences. Intermittent hypoxia might also worsen concomitant tonic hypoxia due to high altitude or due to acute or chronic respiratory diseases by promoting oxidative stress and angiogenesis, thus increasing sympathetic activation with blood pressure elevation, inflammation and endothelial dysfunction. Although OSA and its hypoxic consequence are effectively alleviated with positive airways pressure, this treatment is yet unsatisfactory, being poorly tolerated by up to half of patients. Thus, new treatment strategies are strongly needed. With the aim of better understand OSA physiopathology, key contributors of its development have been identified and include upper airway collapsibility, ventilatory instability, low arousal threshold and reduced pharyngeal dilator muscle responsiveness during sleep, due to loss of noradrenergic drive and enhanced muscarinic influences to upper airway muscles. The recognition of these pathophysiological traits permitted to advance the research in the field of OSA new therapeutic perspectives. Aim: The aim of this study was to evaluate the effect of 1-week of reboxetine (a noradrenergic) plus oxybutynin (an antimuscarinic) on OSA severity (primary outcome) and their effect on endotypic traits and cardiovascular autonomic modulation. Methods: We performed a randomized, placebo-controlled, double-blind, crossover trial comparing 4 mg reboxetine plus 5 mg oxybutynin (reb–oxy) to placebo in OSA subjects. After a baseline in-lab polysomnogram (PSG), patients performed PSGs after 7 nights of reb-oxy and 7 nights of placebo to compare apnea-hypopnea index (AHI, primary outcome). Secondary outcomes included hypoxic burden, heart rate variability, blood pressure and heart rate changes and psychomotor vigilance test. Home oximetry evaluated overnight oxygen desaturation throughout treatment. Results: 16 subjects aged 57[51-61] years (median [interquartile range]) with body mass index 30[26-36] kg/m2 completed the study. Reb-oxy lowered AHI from 49[35-57] events/h at baseline to 18[13-21] events/h (59% median reduction) compared with 39[29-48] events/h (6% median reduction) on placebo (p<0·001). Response rate for reb-oxy was 81% versus 13% for placebo p<0·001). Median nocturnal heart rate during the PSG was 65 [60-69] bpm at baseline and increased to 69 [64-77] bpm on reb-oxy vs 66 [59-70] bpm on placebo (p=0.02). Reb-oxy administration was not associated with any modification in heart rate variability, 24-hour, day-time and night-time systolic and diastolic blood pressure. The psychomotor vigilance test decreased from 250[239-312] ms on baseline to 223[172-244] ms on reb-oxy versus 264[217-284] ms on placebo (p<0·001). Home oximetry illustrated acute and sustained improvement in oxygen desaturation index on reb-oxy versus placebo. Conclusions: The recent understanding of OSA pathophysiological mechanisms brought to hypothesize that, among the others, muscle responsiveness would be the main target to develop a precision medicine to treat OSA. We demonstrated that OSA severity and OSA-related hypoxic consequences are greatly decrease by the administration of reboxetine-plus-oxybutynin. These results highlight potential possibilities for personalized medicine with pharmacological therapy to treat OSA and its related hypoxic burden.

La apnea de la prematurez es el más común de los desórdenes de la respiración en los neonatos. Está relacionada con la edad gestacional y el peso. En recién nacidos que pesan menos de 1500grs, la incidencia de apnea es de aproximadamente 25 a 50% y se aproxima a 90% para los que pesan menos de 1000grs; clasificándose en centrales, obstructivas y mixtas de acuerdo con la ausencia o presencia de movimientos respiratorios3 En nuestro hospital no se cuenta con información sobre las características clínicas y epidemiológicas de los pacientes prematuros menores de 34sdg con apnea; el número de recién nacidos prematuros ha incrementado, hasta en un 40% en las unidades de cuidados intensivos neonatales a nivel mundial, y en nuestro HMI ISSEMyM representa el 25.6% de los ingresos; éstos, con una estancia prolongada, presentarán complicaciones inherentes a prematurez, y tomando en cuenta que es un hospital donde se reciben recién nacidos de unidades periféricas de todo el Estado de México; y con la finalidad de realizar un análisis de los datos obtenidos que nos permitan un mejor conocimiento se realiza el presente estudio. OBJETIVO GENERAL Determinar el perfil clínico y epidemiológico de recién nacidos prematuros menores de 34 semanas de edad gestacional, con diagnóstico de apnea, manejados en el servicio de Neonatología del Hospital Materno Infantil del ISSEMyM en el período del01 enero al 31 de diciembre del 2012 MÉTODO Previo consentimiento del subcomité de Investigación del Hospital, y mediante un diseño de serie de casos, se realizó revisión de expedientes clínicos de Recién Nacidos menores de 34semanas de gestación, quienes ingresaron y presentaron un evento de apnea, con el fin de estudiar las variables clínicas y epidemiológicas. RESULTADOS De los 52 expedientes revisados, encontramos como antecedentes maternos cervicovaginitis en 21 pacientes 35%, y 8 pacientes sin reporte de patología alguna 14%,44 pacientes el 85%, fueron obtenidos por cesárea, el 53% correspondió a 27 masculinos, con una proporción masculino-femenino 1.1:1Respecto al peso al nacimiento, hubo un rango de peso entre 800-2000 gramos al momento del nacimiento, hubo una mayor presentación en neonatos menores de 30 semanas con 13 pacientes 23%. Se observó predominio de apnea mixta que correspondió a 23 pacientes, 44%, seguido de apnea central con 42% y obstructiva de 14%Con respecto a los diagnósticos al recién nacido con apnea, hubo una frecuencia de sepsis con 21 pacientes lo que representó el 34%. En cuanto al tratamiento utilizado, en el 90% de los pacientes no se utilizó profilaxis para apnea. En cuanto al tiempo de estancia intrahospitalaria a partir del diagnóstico se encontró un rango entre 20 y 65 días con una media de 24.2 días y una DE de ±18.3.

Orientador: Maria Valeriana Leme de Moura-Ribeiro
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: O objetivo deste estudo observacional com grupo controle foi: a) verificar a presença de defeitos de desenvolvimento do esmalte (DDE) em dentes decíduos de crianças nascidas pré-termo (PT) e com baixo peso, e um grupo controle de nascidos a termo e com peso normal; b) investigar possíveis fatores etiológicos pré-natais e neonatais associados à presença dos DDE; c) situar as hipoplasias, de acordo com sua localização, como pré-natais ou pós-natais, segundo tabelas de cronologia de mineralização. Cada grupo foi formado por 61 crianças, examinadas entre 18 ¿ 35 meses de idade; todas nascidas no Centro de Atenção Integral à Saúde da Mulher ¿ Universidade Estadual de Campinas. Foi adotado o critério da FDI para a avaliação odontológica. Os dados da história médica foram colhidos retrospectivamente do prontuário do hospital. A análise estatística dos dados foi realizada através dos testes de Mann-Whitney, qui-quadrado e exato de Fisher. A freqüência encontrada entre pré-termos foi 57.4% de DDE, 52.5 % de opacidades e 21.3 % de hipoplasia. No grupo controle, 24.6% apresentaram DDE, 24.6% tiveram opacidades e 3.3%, hipoplasia. Os DDE estiveram significativamente associados com o nascimento PT e com baixo peso (p <0.001). Após a regressão logística multivariada, a apnéia permaneceu como a variável mais associada aos DDE. Pode-se concluir que crianças nascidas PT e com baixo peso apresentaram maior prevalência de DDE que aquelas nascidas a termo e com peso normal. O fator neonatal apnéia teve associação significativa com DDE. No entanto, cumpre ressaltar que utilizando os DDE como marcadores biológicos, estes defeitos localizados na porção de esmalte formado no período pré-natal indicam uma agressão sistêmica ocorrida neste período. Existem muitos aspectos a serem considerados na prematuridade ou no recém-nascido submetido a um processo hipóxico-isquêmico. Os DDE, utilizados como marcadores biológicos, podem ser um dado a mais na compreensão dos fatores sistêmicos envolvidos na prematuridade ou na lesão do SNC e suas conseqüências
Abstract: The purpose of this observational study with control group was: a) verify the presence of developmental enamel defects (DDE) in deciduous teeth of infants born preterm (PT) and with low birthweight and in a control group of infants born full term and with normal birthweight; b) investigate possible prenatal and postnatal etiologic factors associated with DDE; c) classify hypoplasias according to their location as prenatal or postnatal, following mineralization tables. Each group was formed by 61 children, examined between 18 and 35 months of age; all born at the Center for Integral Assistance to Women¿s Health ¿ State University of Campinas. FDI criteria were followed for dental examination. Medical data was collected retrospectively from hospital records. The statistic analysis was performed with the Mann-Whitney, chi-square and Fisher¿s exact test, wherever appropriate. Among preterms, 57.4% had some type of DDE, 52.5 % had opacities and 21.3 % presented hypoplasia. Among full terms, 24.6% presented DDE, 24.6% had opacities and 3.3% had hypoplasia. DDE were significantly associated with preterm birth and low birth weight (p< 0.001). After the multivariate logistic regression, apnea remained as the variable most strongly associated with DDE. Concluding, infants born preterm and with low birthweight presented a higher prevalence of DDE than those born full term and with normal birth weight. The neonatal variable apnea presented a statistically significant association with DDE. Nevertheless, using DDE as biological markers, the defects observed in the tooth enamel formed during the neonatal period indicate that a systemic insult occurred in this period. There are many aspects that must be considered in prematurity and in infants that suffered hypoxic ischemic insults. DDE, used as biological markers, may be an additional element in the study of the variety of factors involved in prematurity or insults to the Central Nervous System and its consequences
Mestrado
Ciencias Biomedicas
Mestre em Ciências Médicas

Objectives: Altered dentofacial morphology has been suggested as an etiology for childhood OSA. Nevertheless, existing reports on the dentofacial characteristics of children with OSA vary significantly and are limited by the infrequent use of polysomnography (PSG) for diagnosis. Therefore, the objective of this study is to establish the prevalence of dentofacial morphology in children with OSA diagnosed using PSG. Methods: The sample comprised 64 children between the ages of 4-16 who were referred to BC Children’s Hospital for PSG. Diagnosis of OSA was provided by an overnight, in-laboratory PSG. Malocclusion was assessed clinically by one orthodontist (K.L.), blinded to PSG results. Results: Children with previous orthodontic treatment were excluded and children with craniofacial syndromes were analyzed separately. The 17 patients with craniofacial syndromes presented a significantly different dentofacial features and higher prevalence of OSA when compared to the non-syndromic children. The remaining 39 patients were divided into an OSA group (AHI ≥ 2; n=17) and a non-OSA group (AHI < 2; n=22). There were no statistically significant differences in frequency of any dentofacial features between the two groups, although the OSA group had a lower prevalence of convex profile, Class II molar relationship, and overjet (OJ) ≥ 5mm. Subjects in the OSA group were further divided into a lower AHI (AHI between 2-5; n=9) group and a higher AHI group (AHI ≥ 5; n=8). There was no statistically significant difference in frequency of any dentofacial features between the three groups. Nevertheless, subjects in the higher AHI group had a lower prevalence of convex profile and poster crossbite, with less crowding and smaller OJ on average. Conclusions: In this patient population of 39 children between the ages of 4-16 who were referred to BCCH for an overnight sleep study, no statistically significant differences in dentofacial morphology and occlusal characteristics were found between children diagnosed with and without OSA. It is likely that children with OSA have a highly variable presentation of anatomical features, and future studies with a larger sample size and a true control group is needed to establish the dentofacial morphology of this population.
Dentistry, Faculty of
Graduate

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Current research has shown that an increasing number of returning troops from deployments are being diagnosed with obstructed sleep apnea (OSA). OSA causes excessive daytime sleepiness that can endanger the readiness of Soldiers by impacting concentration, decision-making skills, personality change, hypertension, depression, headaches and has been shown to contribute to cardiovascular disease. A main factor for remediation of OSA is Soldier’s compliance with prescribed treatment plans. The two most popular methods for OSA treatment are continuous positive airway pressure (CPAP) and the Mandibular Advancing Device (MAD). Both of these devices have known compliance issues, which keep treatment of OSA to roughly 60 percent of those prescribed. We utilized a parameterized upper airway fluid structure–interaction (FSI) simulation to validate our hybrid OSA device (MAPPARD), which addressed the compliance issues found in typical OSA treatment devices. While being 25 percent less advanced than the MAD device and 50 percent less pressure than the CPAP device, our MAPPARD performed better than either current device, thus showing potential to improve Soldier treatment compliance. This study contributes to the ongoing exploration of the role of modeling and simulations for testing and evaluation of medical devices.

Thesis (M.S.) -- Central Connecticut State University, 2008.
Thesis advisor: Ruth Rollin. "... in partial fulfillment of the requirements for the degree of Master of Science in Biology." Includes bibliographical references (leaves 39-41). Also available via the World Wide Web.

Abstract In Finland, the costs of stroke are approximately 1.1 billion euros annually due to long disability and hospitalization episodes. Sleep apnea is a risk factor for stroke. The prevalence of sleep apnea among stroke patients is unknown because sleep recording is not usually performed on stroke patients. There are no previous studies investigating the association of thrombolysis on the prognosis of sleep apnea. The relation between sleep apnea and cardiovascular events is still unclear. In this prospective, observational study, I recruited voluntary, consecutive ischemic stroke patients over the age of 18 years who were or were not eligible for thrombolysis treatment. The investigators did not affect the treatment and patients were not randomized to thrombolysis. The final analysis included 204 patients; of these, 110 underwent thrombolysis therapy and 94 were treated without thrombolysis. Cardiorespiratory polygraphy was carried out with a portable three-channel device (ApneaLinkPlus™, Resmed, Sydney, Australia) at the ward within 48 hours after the onset of stroke symptoms. The cardiorespiratory polygraphy was repeated at home after a six-month follow-up. Both automatic scoring and manual scoring pointed out excellent agreement in arterial oxyhemoglobin decrease of > 4% (ODI4), lowest arterial oxyhemoglobin saturation (SaO2) or percentage of time spent below 90 percent saturation. The automated scoring underestimated the severity of sleep apnea, recognized poorly the type of event, and missed 18.6% of sleep apnea diagnoses. The total prevalence of sleep apnea in this study was 91.2% on admission to hospital. The stroke patients treated with thrombolysis had more, and more severe sleep apnea in the first sleep recording compared to those without thrombolysis therapy. After follow-up, the prevalence of sleep apnea still remained high, and sleep apnea was aggravated in two thirds of the stroke patients. The study patients without thrombolysis treatment had six-fold higher risk for incident sleep apnea after the follow-up. The stroke patients with thrombolysis therapy and visible stroke on CT had more nocturnal hypoxemia and higher obstructive apnea index than the patients without stroke lesion on follow-up CT 24 hours after thrombolysis treatment. The larger the ischemic stroke volume, the greater the time spent with saturation below 90%
Tiivistelmä Aivoinfarkti on yleinen ja kansanterveydellisesti sekä taloudellisesti merkittävä sairaus, jonka aiheuttamat kustannukset Suomessa ovat noin 1.1 miljardia euroa pitkistä työkyvyttömyys- ja sairaalajaksoista johtuen. Uniapnea on aivoinfarktille altistava tekijä. Uniapnean esiintyvyys suomalaisilla aivoinfarktipotilailla ei ole arvioitavissa, koska aivoinfarktin sairastaneille ei yleensä tehdä unirekisteröintiä. Kannettavat yöpolygrafialaitteet saattaisivat olla vaihtoehto aivoinfarktipotilaiden uniapnean diagnosoinnille. Tutkittua tietoa liuotushoidon yhteydestä uniapnean ennusteeseen ei ole. Uniapnean sekä sydän- ja verisuonitapahtumien syy-yhteys on edelleen epäselvä. Rekrytoin prospektiiviseen tutkimukseeni vapaaehtoisia, peräkkäisiä yli 18-vuotiaita iskeemiseen aivoinfarktiin sairastuneita liuotushoidettuja ja liuotushoitoon soveltumattomia potilaita. Tutkimuksen lopullinen potilasmäärä oli 204, joista 110 sai liuotushoidon ja 94 hoidettiin ilman liuotusta. Kaikille potilaille tehtiin yöpolygrafia kannettavalla, kolmikanavaisella yöpolygrafialaitteella (Apnealink Plus, Resmed, Sydney, Australia) osastolla 48 tunnin kuluessa sairastumisesta. Yöpolygrafia toistettiin potilaan kotona kuuden kuukauden kuluttua. Sekä automaattitulos että manuaalisesti arvioitu unirekisteröintitulos olivat erittäin yhteneväisiä, kun arvion kohteena olivat happikyllästeisyyden neljän prosenttiyksikön suuruiset pudotukset tuntia kohti, matalin veren happikyllästeisyys tai alle 90 % happikyllästeisyyden osuus yöstä. Automaattianalyysi aliarvioi uniapnean vaikeuden, havaitsi huonosti hengityskatkosten tyypin eikä löytänyt 18,6 prosenttia uniapneadiagnooseista. Uniapnean esiintyvyys koko aineistossa oli sairaalaan tullessa 91,2 %. Liuotushoidetuilla potilailla todettiin ensimmäisessä rekisteröinnissä enemmän uniapneaa ja se oli vaikeampaa kuin ei-liuotushoidetuilla. Seurannassa uniapnean määrä pysyi edelleen korkeana ja uniapnea vaikeutui kahdella potilaalla kolmesta. Liuotushoitoon soveltumattomilla aivoinfarktipotilailla todettiin liuotushoidon saaneisiin verrattuna kuusinkertainen riski sairastua uniapneaan puolen vuoden aikana. Liuotushoidetuilla aivoinfarktipotilailla, joilla oli infarktimuutos kuvantamistutkimuksessa, oli yöllistä valtimoveren happikyllästeisyyden huononemista ja ylähengitysteiden ahtautumisesta johtuvia hengityskatkoksia enemmän kuin niillä potilailla, joilla ei todettu iskeemisiä muutoksia aivokuvantamisessa 24 tuntia liuotushoidon jälkeen. Mitä suurempi aivoinfarktin tilavuus, sitä suuremman osuuden yöstä veren happikyllästeisyys oli alle 90 %

Thesis (M.S.)--West Virginia University, 2004.
Title from document title page. Document formatted into pages; contains vii, 47 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 30-31).

Obstructive Sleep Apnoea (OSA) is a disease characterised by repetitive upper airway obstructions which are manifest by desaturation and arousal from sleep. It has been known for many years that this interruption to the normal architecture of sleep may present to the clinician as excessive daytime somnolence often with a complaint of difficulties with concentration and short term memory. Previous work had demonstrated a relationship between variables of cognitive dysfunction in patients with obstructive sleep apnoea, however, little was known about which components of the syndrome contributed to this outcome and whether specific clinical thresholds of sleep disordered breathing could be defined for the development of cognitive dysfunction. In the context of this body of work cognitive dysfunction is defined as: a level of cognitive performance below normal derived values for a given cognitive test, when the subjects performance is controlled for age, sex and level of education.

Obstructive Sleep Apnoea (OSA) is a disease characterised by repetitive upper airway obstructions which are manifest by desaturation and arousal from sleep. It has been known for many years that this interruption to the normal architecture of sleep may present to the clinician as excessive daytime somnolence often with a complaint of difficulties with concentration and short term memory. Previous work had demonstrated a relationship between variables of cognitive dysfunction in patients with obstructive sleep apnoea, however, little was known about which components of the syndrome contributed to this outcome and whether specific clinical thresholds of sleep disordered breathing could be defined for the development of cognitive dysfunction. In the context of this body of work cognitive dysfunction is defined as: a level of cognitive performance below normal derived values for a given cognitive test, when the subjects performance is controlled for age, sex and level of education.

Orientador: Altair Antoninha Del Bel Cury
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba
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Resumo: Distúrbios respiratórios do sono são condições patológicas freqüentes. Dentre estes, destaca-se o Ronco Primário que quase sempre causa conflitos sociais e familiares, podendo ocorrer isoladamente ou fazendo parte de um quadro clínico mais severo, a Síndrome da Apnéia Obstrutiva do Sono. Esta por sua vez, além da presença do ronco que ocorre em mais de 90% dos casos, é também caracterizada por paradas respiratórias, microdispertares, dessaturações de oxigênio sanguíneo, desestruturação do sono, sonolência diurna importante, aumento da possibilidade de hipertensão arterial sistêmica, infarto do miocárdio, acidente vascular encefálico, envolvimento em acidentes de trabalho e de trânsito, assim como comprometimento da memória, cognição e atenção. A Síndrome da Apnéia Obstrutiva do Sono pode ser subdividida em três níveis (leve, moderada e grave), considerando o índice de apnéia/hipopnéia. As formas de tratamento incluem principalmente a cirurgia, pressão aérea positiva contínua (CPAP) e aparelhos intraorais. Este estudo investigou com o exame de polissonografia, os efeitos do uso de aparelho intraoral de protrusão mandibular, em onze voluntários com idade entre 23 e 62 anos, sendo 63,6% do gênero masculino e 36,4% feminino. Destes, dois apresentavam ronco primário, dois apnéia grave, quatro apnéia moderada e três apnéia leve. Os pacientes foram avaliados através de polissonografia, antes e após o uso do aparelho intraoral, tendo sido estudadas as seguintes variáveis: índices de apnéia/hipopnéia, dessaturação de oxigênio, número de apnéias, número de hipopnéias e ronco. Este foi avaliado quanto à intensidade e freqüência esporádica ou ausente. Na Análise Estatística foi utilizado o teste t de Student para as variáveis: índice de Apnéia e Hipopnéia, Saturação Mínima de Oxigênio, Número total de Apnéias e Número Total de Hipopnéias. As variáveis Escala de Graduação do Ronco, Grau de Sonolência Diurna e Ruído do Ronco, foram analisadas pelo Teste de Wilcoxon das ordens assinaladas, com intervalo de confiança de 95%. Em todas as análises foi adotado um nível de significância de 5% (a =0,05). Os resultados mostraram que todos os voluntários tiveram redução significativa nas variáveis estudadas. Todos os indivíduos com Ronco Primário obtiveram resolução completa do problema. No grupo de Apnéia leve, todos os voluntários passaram a apresentar exame de polissonografia normais; Apnéia moderada, 75% também obtiveram exame normal e em 25% a apnéia passou de grau moderado para leve. Considerando os que apresentavam Apnéia grave, 50% passaram a apresentar apnéia moderada e 50% apnéia leve. Dessa forma pode-se concluir que o uso de aparelho intraoral é uma forma de tratamento eficiente para o ronco primário e apnéia obstrutiva do sono
Abstract: Snoring is a noise that occurs during sleep when the people are breathing in and there is some blockage of air passing through the back of the mouth and it is a frequent pathological conditions called Primary Snore. This snore can be or not be associated with more serious problems, such as obstructive sleep apnea syndrome (OSAS), frequent arousals from sleep, or inability of the lungs to breathe in sufficient oxygen. It is also characterized by excessive daytime sleepiness or fatigue. Patients also may complain of difficulty with concentration, morning headaches, impotence, difficulty sleeping, or restless sleep. Obstructive Sleep Syndrome Apnea can be subdivided in three levels (Iight, moderate and serious), considering the apnea/hipopnea index. The treatment forms include surgery, positive aerial pressure continuous (CPAP) and oral appliance. This study investigated the effects of the use of oral appliance by moving either the tongue or the mandible anteriorly, partially relieving apneas in eleven volunteers with age between 23 and 62 years, being 63,6% of the male gender and 36,4% of female. The volunteers were undergo polysomnography exam, Scale of Graduation of the Snore, Epworth Sleepiness Scale and Snore. After these exams two volunteers were diagnosed as primary snore, two serious apnea, four moderate apnea and three light apnea. The patients were appraised through ali exams before (TO) and after (T1) the use of the oral appliance. The data were statistically analyzed by t Student test for Apnéia I Hypopnea Index, Minimum Saturation of Oxygen, total Number of Apneas and Total Number of Hypopneas and by Wilcoxon signaled orders test to Scale of Graduation of the Snore, Epworth Sleepiness Scale and Snore, they were analyzed by the Test of Wilcoxon with 95% levei of confidence. The results showed that ali the volunteers had significant reduction in the studied variables. Ali the individuais with Primary Snore obtained complete resolution of their problem. Also the volunteers suffering from OSAS had a reduction in their polysomnography exams. Within the limits of this study, it can be concluded that the use of oral appliance was efficient treatment to the Primary Snore and Obstructive Sleep Syndrome Apnea
Mestrado
Protese Dental
Mestre em Clínica Odontológica

La síndrome d'apnea-hipopnea de la son (SAOS) afecta més d'un 10% de la població adulta, i aquesta prevalença va augmentant amb l'edat. El SAOS es caracteritza per episodis repetits d'obstrucció de la via aèria superior durant el son, causant hipoxèmia intermitent i interrupció del son. El SAOS es relaciona amb un deteriorament de la qualitat de vida, somnolència diürna excessiva, malalties cardiovasculars i cerebrovasculars, ia més amb un excés de mortalitat, principalment per malaltia cardiovascular i càncer. Quant als factors de risc, l'edat, el sexe masculí i l'índex de massa corporal són els més importants. Cada esdeveniment apnéico finalitza amb un arousal (despertar electroencefalogràfic). Els episodis d'hipòxia intermitent i els arousals provoquen un augment de l'activitat simpàtica i canvis sobtats de la pressió arterial, que contribueixen al desenvolupament d'hipertròfia miocàrdica, arítmies cardíaques i mort per causa cardiovascular. A més, aquests episodis repetits d'hipòxia-reoxigenació, i l'augment de l'activitat simpàtica poden activar diferents vies patogèniques que afavoreixen la carcinogènesi com són: estrès oxidatiu, inflamació sistèmica i activació del factor induït per la hipòxia. Aquestes alteracions fisiològiques explicarien el major risc de desenvolupar malaltia cardiovascular i càncer en pacients amb SAOS. No obstant això el SAOS sembla no contribuir de la mateixa manera en tots els pacients en el desenvolupament de malaltia cardiovascular i de càncer. D'altra banda, el diagnòstic de SAOS és complex i requereix d'una prova nocturna que ha de ser avaluada per experts. Els qüestionaris que intenten diferenciar al pacient SAOS té una habilitat de discriminació baixa, fent difícil el cribratge i el diagnòstic ràpid de la SAOS. L'objectiu de la present tesi és avaluar l'ús de biomarcadors en el maneig del pacient amb SAOS tant a nivell de diagnòstic, com per estratificar el risc cardiovascular i carcinogènic dels mateixos. En el primer estudi de la present tesi es van identificar microRNAs (miRNAs) circulants que fossin estables en pacients amb i sense SAOS i que permetin homogeneïtzar els resultats i reduir la variabilitat tècnica. En el segon estudi es va avaluar el perfil circulant de miRNAs per al diagnòstic del pacient amb SAOS i es va trobar una empremta de miRNAs que permet discriminar al pacient SAOS amb més precisió que els qüestionaris actuals. A més, es van identificar una sèrie de miRNAs que canviaven amb el tractament amb pressió contínua positiva de la via aèria (CPAP). En el tercer estudi no es va trobar un perfil de miRNAs capaç de distingir grups amb diferent risc cardiovascular dins dels pacients SAOS. Tot i això, es van identificar dos miRNAs que estaven associats amb paràmetres de pressió arterial en els pacients amb SAOS. Finalment, en el quart estudi es va observar, que en pacients amb melanoma cutani el SAOS s'associa amb un increment en els nivells sanguinis de VCAM-1 que podria indicar la contribució de la SAOS en la tumorigènesi via adhesió per integrines. En resum, en la present tesi s'ha avançat en l'ús de la medicina de precisió en els pacients amb SAOS. I s'ha observat que mitjançant l'anàlisi de biomarcadors circulants, a partir d'una sola mostra sanguínia es podria avaluar massivament si el pacient té altes probabilitat de tenir SAOS o no, si pot tenir elevada la pressió arterial nocturna i si tenen un major risc de carcinogènesi i creixement tumoral. Una segona mostra sanguínia, permetria valorar els canvis a nivell molecular dels pacients amb el tractament.
El síndrome de apnea-hipopnea del sueño (SAOS) afecta a más de un 10% de la población adulta, y dicha prevalencia va aumentando con la edad. El SAOS se caracteriza por episodios repetidos de obstrucción de la vía aérea superior durante el sueño, causando hipoxemia intermitente e interrupción del sueño. El SAOS se relaciona con un deterioro de la calidad de vida, somnolencia diurna excesiva, enfermedades cardiovasculares y cerebrovasculares, y además con un exceso de mortalidad, principalmente por enfermedad cardiovascular y cáncer. En cuanto a los factores de riesgo, la edad, el sexo masculino y el índice de masa corporal son los más importantes. Cada evento apnéico finaliza con un arousal (despertar electroencefalográfico). Los episodios de hipoxia intermitente y los arousals provocan un aumento de la actividad simpática y cambios repentinos de la presión arterial, que contribuyen al desarrollo de hipertrofia miocárdica, arritmias cardíacas y muerte por causa cardiovascular. Además, dichos episodios repetidos de hipoxia-reoxigenación, y el aumento de la actividad simpática pueden activar diferentes vías patogénicas que favorecen la carcinogénesis como son: estrés oxidativo, inflamación sistémica y activación del factor inducido por la hipoxia. Estas alteraciones fisiológicas explicarían el mayor riesgo de desarrollar enfermedad cardiovascular y cáncer en pacientes con SAOS. No obstante el SAOS parece no contribuir de igual forma en todos los pacientes en el desarrollo de enfermedad cardiovascular y de cáncer. Por otro lado, el diagnóstico de SAOS es complejo y requiere de una prueba nocturna que ha de ser evaluada por expertos. Los cuestionarios que intentan diferenciar al paciente SAOS tiene una habilidad de discriminación baja, haciendo difícil el cribado y el diagnóstico rápido del SAOS. El objetivo de la presente tesis es evaluar el uso de biomarcadores en el manejo del paciente con SAOS tanto a nivel de diagnóstico, cómo para estratificar el riesgo cardiovascular y carcinogénico de los mismos. En el primer estudio de la presente tesis se identificaron microRNAs (miRNAs) circulantes que fueran estables en pacientes con y sin SAOS y que permitan homogeneizar los resultados y reducir la variabilidad técnica. En el segundo estudio se evaluó el perfil circulante de miRNAs para el diagnóstico del paciente con SAOS y se encontró una huella de miRNAs que permite discriminar al paciente SAOS con mayor precisión que los cuestionarios actuales. Además, se identificaron una serie de miRNAs que cambiaban con el tratamiento con presión continua positiva de la vía aérea (CPAP). En el tercer estudio no se encontró un perfil de miRNAs capaz de distinguir grupos con diferente riesgo cardiovascular dentro de los pacientes SAOS. A pesar de ello, se identificaron dos miRNAs que estaban asociados con parámetros de presión arterial en los pacientes con SAOS. Por último, en el cuarto estudio se observó, que en pacientes con melanoma cutáneo el SAOS se asocia con un incremento en los niveles sanguíneos de VCAM-1 que podría indicar la contribución del SAOS en la tumorigénesis vía adhesión por integrinas. En resumen, en la presente tesis se ha avanzado en el uso de la medicina de precisión en los pacientes con SAOS. Y se ha observado que mediante el análisis de biomarcadores circulantes, a partir de una sola muestra sanguínea se podría evaluar masivamente si el paciente tiene altas probabilidad de tener SAOS o no, si puede tener elevada la presión arterial nocturna y si tienen un mayor riesgo de carcinogénesis y crecimiento tumoral. Una segunda muestra sanguínea, permitiría valorar los cambios a nivel molecular de los pacientes con el tratamiento.
Apnea-hypopnea sleep syndrome (OSA) affects more than 10% of the adult population, and this prevalence increases with age. OSA is characterized by repeated episodes of upper airway obstruction during sleep, causing intermittent hypoxemia and sleep disruption. OSA is related to a deterioration in the quality of life, excessive daytime sleepiness, cardiovascular and cerebrovascular diseases, and also with an excess of mortality, mainly due to cardiovascular disease and cancer. Regarding risk factors, age, male sex and body mass index are the most important. Each apneic event ends with an arousal (electroencephalographic awakening). Episodes of intermittent hypoxia and arousals cause an increase in sympathetic activity and sudden changes in blood pressure, which contribute to the development of myocardial hypertrophy, cardiac arrhythmias and cardiovascular death. In addition, these repeated episodes of hypoxia-reoxygenation, and the increase in sympathetic activity can activate different pathogenic pathways that favor carcinogenesis such as: oxidative stress, systemic inflammation and hypoxia-induced factor activation. These physiological alterations would explain the increased risk of developing cardiovascular disease and cancer in patients with OSAS. However, SAOS does not seem to contribute equally to all patients in the development of cardiovascular disease and cancer. On the other hand, the diagnosis of OSA is complex and requires a night test that has to be evaluated by experts. Questionnaires that attempt to differentiate the SAOS patient have a low discrimination ability, making screening and rapid diagnosis of OSA difficult. The objective of this thesis is to evaluate the use of biomarkers in the management of patients with OSAS both at the diagnostic level, and to stratify their cardiovascular and carcinogenic risk. In the first study of this thesis, circulating microRNAs (miRNAs) were identified that were stable in patients with and without OSAS and that allowed homogenizing the results and reducing technical variability. In the second study, the circulating profile of miRNAs for the diagnosis of the patient with OSA was evaluated and a footprint of miRNAs was found that allows the OSA patient to be discriminated more accurately than the current questionnaires. In addition, a series of miRNAs were identified that changed with the treatment with positive continuous airway pressure (CPAP). In the third study, there was no profile of miRNAs able to distinguish groups with different cardiovascular risk within OSAS patients. Despite this, two miRNAs were identified that were associated with blood pressure parameters in patients with OSA. Finally, in the fourth study it was observed that in patients with cutaneous melanoma, OSA is associated with an increase in blood levels of VCAM-1 that could indicate the contribution of OSA in tumorigenesis via integrin adhesion. In summary, in this thesis progress has been made in the use of precision medicine in patients with OSA. And it has been observed that through the analysis of circulating biomarkers, from a single blood sample it could be massively evaluated if the patient has a high probability of having OSA or not, if he can have elevated nocturnal blood pressure and if they have a higher risk of Carcinogenesis and tumor growth. A second blood sample would allow to assess the changes at the molecular level of the patients with the treatment.

Rationale. Hypertension occurs in 10% of pregnancies. Snoring is a marker for sleep apnea, and is a newly identified risk factor for gestational hypertension. Moreover, sleep apnea is an independent risk factor for hypertension in the non-pregnant population. I hypothesized that sleep apnea was associated with gestational hypertension.
Hypothesis. The prevalence of sleep apnea is higher among pregnant women with hypertensive pregnancies than among those without hypertension during pregnancy.
Design. Case-control study of 17 pregnant women with gestational hypertension and 33 pregnant women without hypertension, with matching by gestational age. Sleep apnea was ascertained by polysomnography.
Results. The crude odds ratio for the presence of obstructive sleep apnea, given the presence of gestational hypertension, was 5.6. The odds ratio was 7.5 (95% CI 3.5-16), based on a logistic regression model with adjustment for maternal age, gestational age, nulliparity, first pregnancy, and body mass index.
Conclusion. Gestational hypertension was strongly associated with the presence of obstructive sleep apnea.

Background: Snoring and obstructive sleep apnea (OSA) are both common disorders with a number of negative health effects. The safety and efficacy of treating snoring and OSA surgically have been questioned and there has been a lack of studies in the field. Aims: 1) To investigate the frequency of serious complications, including death, after surgery for the treatment of snoring and sleep apnea; 2) to evaluate the effect on daytime sleepiness after radiofrequency surgery of the soft palate in snoring men with mild or no OSA; 3) to evaluate the effect of tonsillectomy on sleep apnea in adults with OSA and tonsillar hypertrophy; 4) to investigate the morphology and cytoarchitecture of muscle fibers in human soft palatal muscles with immunohistochemical and morphological techniques. Methods and results: In paper 1, a retrospective database study. All Swedish adults who were treated surgically because of snoring or OSA from January 1997 to December 2005 were identified in the National Patient Register. None of the surgically treated patients died in the peri- and postoperative period. Severe complications were recorded in 37.1 of 1,000 patients treated with uvulopalatopharyngoplasty (UPPP), in 5.6 of 1,000 patients after uvulopalatoplasty (UPP) and in 8.8 of 1,000 patients after nasal surgery. In paper 2, the study was designed as a randomized, controlled trial. 35 snoring men with mild or no OSA were randomized to either radiofrequency or sham surgery of the soft palate. Radiofrequency surgery was not found to be effective since there was no significant difference between the two groups in relation to the Epworth Sleepiness Scale (ESS) or apnea-hypopnea index (AHI) at follow-up. Paper 3 was a prospective study, including 28 patients with an AHI of >10 and with large tonsils. In these patients, tonsillectomy was an effective treatment for OSA; the mean AHI was reduced from 40 units/h to 7 units/h (p<0.001), and the mean ESS was reduced from 10.1 to 6.0 (p<0.001) at the six-month follow-up after surgery. Minor and moderate swallowing dysfunction was found in seven of eight patients investigated before surgery and the swallowing function improved in 5 of them after surgery, while no one deteriorated. In paper 4, we investigated the morphology and cytoarchitecture in normal soft palate muscles. Human limb muscles were used as reference. The findings showed that the soft palate muscle fibers have a cytoskeletal architecture and cellmembrane complex that differs from that of the limb muscles. Conclusions No case of death related to surgery was found among 4,876 patients treated with UPPP, UPP or nasal surgery for snoring or OSA in Sweden between 1997 and 2005. Radiofrequency surgery of the soft palate has no effect on daytime sleepiness, snoring or apnea frequency in snoring men with mild or no OSA. Tonsillectomy can be an effective treatment for OSA in adults with large tonsils. A subgroup of muscle fibers in the human soft palate appears to have special biomechanical properties and their unique cytoarchitecture must be taken into account while assessing function and pathology in oropharyngeal muscles.
Snarkning och obstruktiv sömnapné (OSA) är idag en global folksjukdom. Snarkning är det ”oljud” som uppstår när luftvägen under sömn förminskas och vävnaden börjar vibrera under andning. Vid obstruktiv sömnapné faller vävnaden samman och blockerar luftflödet till lungorna. Ett andningsuppehåll, en s.k. apné inträffar. Ett andningsuppehåll kan pågå allt ifrån några sekunder till mer än en minut och kan uppstå hundratals gånger per natt. För att klassificeras som en patologisk apné enligt internationell standard måste andningsuppehållet vara längre än 10 sek. Snarksjukdomen förvärras sannolikt över tid och övergår succesivt i obstruktiv sömnapné med ökande antal andningsuppehåll under sömn. Detta leder till ett stresspåslag för kroppen med oftast uttalad dagtrötthet och en mängd negativa hälsoeffekter. Snarksjukdom och sömnapné ökar risken för bl.a. högt blodtryck och hjärt-kärlsjukdom samt också för att den drabbade ska orsaka trafikolyckor på grund av försämrad koncentrationsförmåga och trötthet. En del av den negativa utvecklingen från snarkning till sömnapné anses bero på att snarkvibrationer kan ge neuromuskulära skador i gom och svalg. Dessa vävnadsskador anses också vara orsaken till att personer som snarkat länge ofta uppvisar störd sväljningsfunktion i form av felsväljning, där maten i uttalade fall hamnar i luftstrupen istället för i matstrupen. I dagsläget är förstahandsbehandling vid sömnapné CPAP, en mask som placeras över näsa och mun och som skapar ett övertryck i luftvägen vilket förhindrar att luftvägen faller samman och att andningsstopp uppstår. CPAP har enligt flera studier den bästa effekten mot andningsuppehåll. En annan vanlig behandling är en bettskena som för underkäken nedåt och framåt så att luftvägen bli mer öppen. Bettskenan är en vanlig och effektiv behandlingsmetod för personer utan kraftig övervikt vid vanemässig snarkning eller måttlig sömnapné. För ett tjugotal år sedan var kirurgi förstahandsmetoden vid behandling av snarkning och måttlig sömnapné. Man utförde då ofta operationer i svalg och gomm, s.k. gomplastiker. Bruket av kirurgisk behandling har dock minskat med tiden, dels p.g.a. biverkningar men också för att det saknades vetenskapliga studier som bevisade att kirurgin gav önskad och långsiktig effekt. Kirurgi utgör dock fortfarande ett komplement till behandling av snarkning och sömnapné när CPAP eller bettskena av olika skäl inte fungerar eller kan tolereras av patienten. 8 Även barn kan lida av snarkning och sömnapné men behandlingsprinciperna för barn skiljer sig från dem hos vuxna och berörs inte i avhandlingen. I denna avhandling studeras: i) biverkningsfrekvenser efter olika typer av snarkkirurgi, ii) effekten av radiovågsbehandling i mjuka gommen på vuxna män med snarkning, iii) effekten av att operera bort halsmandlarna på vuxna med sömnapné och stora halsmandlar, iv) muskelvävnadens struktur och molekylära uppbyggnad i mjuka gommen hos friska personer som inte snarkar. Avhandlingen består av fyra delstudier: 1. En registerstudie med kartläggning av svåra biverkningar efter kirurgi i form av uvulopalatopharyngoplastik, uvulupalatoplastik samt näskirurgi för behandling av sömnapné och snarkning och utfört i Sverige mellan åren 1997-2005. Studien omfattade 4 876 patienter. Inga dödsfall noterades. Komplikationsrisken var störst vid operationer där man tog bort delar av mjuka gommen samt halsmandlarna, där i snitt 37 av 1000 opererade fick biverkningar, framförallt p.g.a. infektioner eller blödningar. 2. I en prospektiv, randomiserad placebostudie utvärderades effekten av radiovågsbehandling i mjuka gommen vid snarkning och lindrig sömnapne. Trettiotvå patienter lottades till att få radiovågsbehandling eller placebo behandling. Patienterna visste inte vilken grupp de tillhörde. Vid uppföljning efter 12 månader var det inga statistiska belägg för att radiovågsbehandling minskade vare sig antal andningsuppehåll eller dagtrötthet. 3. Effekten av att ta bort halsmandlarna på patienter med stora halsmandlar och olika grad av sömnapné utvärderades i denna studie. Totalt deltog 28 patienter. Vid uppföljning 6 månader efter operationen hade antalet andningsuppehåll sjunkit drastiskt, från i snitt 40 till 7 andningsuppehåll per timme nattsömn. Inga allvarliga biverkningar uppstod. Dessa fynd talar för att man som förstahandsmetod ska erbjuda patienter med sömnapné och stora halsmandlar att ta bort halsmandlarna. 4. I detta projekt undersökte vi utseendet och uppbyggnaden av cellskelettet i två normala muskler i mjuka gommen hos friska personer utan känd snarkning och sömnapné. Muskler från armar och ben användes som referens. Fynden i studien visar att de normala muskelfibrernas uppbyggnad i mjuka gomen skiljer sig från jämförade muskler i armar och ben. Detta kan vara ett uttryck för en evolutionär utveckling för att möjligöra de komplexa funktioner som krävs av svalgets muskulatur. 9 Sammanfattningsvis kan vi konstatera: Att inga dödsfall har skett i Sverige efter operationer i gom, svalg eller näsa, utförda för att behandla snarkning och sömnapné under åren 1997 till 2005. Att radiovågsbehandling av mjuka gommen hos snarkande män med lindrig sömnapné inte har någon effekt på dagtrötthet, snarkning eller andningsuppehåll vid uppföljning efter 12 månader. Metoden kan därför inte rekommenderas. Att när man opererar bort stora halsmandlar på personer med andningsuppehåll så leder detta ofta till att andningsuppehållen minskar drastiskt. Metoden kan därför oftast rekommenderas som en förstahandsbehandling för denna patientgrupp. Att mjuka gommens muskelfibrer är uppbyggda på ett unikt sätt indikerar att deras specifika biomekaniska egenskaper skiljer sig från referens muskler i armar och ben.

The purpose of the current study was to test the hypothesis that chronic hypoxia associated with sleep-disordered breathing relates to abnormal Nitric Oxide (NO) production and vascular endothelial growth factor (VEGF) expression patterns that contribute to aberrancy of specific determinates of cardiovascular and cardiopulmonary function before, during, and after graded exercise. These patterns may further reflect pathologic alteration of signaling within the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt-1) transduction network. To this end, 7 medically diagnosed OSA patients (3 male, 4 female), mean age 48 years and 7 apparently healthy control subjects (3 male, 4 female), mean age 42 years, underwent baseline venous blood draws and maximal bicycle ergometry. Mononuclear cells isolated from peripheral blood were utilized as reporter cells for measurement of VEGF, Akt-1, hypoxia inducible factor-1 alpha (HIF-1 alpha), and vascular endothelial growth factor receptor-2 (VEGFR2) gene expression by redundant oligonucleotide DNA microarray and real-time PCR technologies. Circulating angiogenic progenitor cells expressing VEGFR2 were profiled by flow cytometry. Plasma and serum concentrations of VEGF, nitrates/nitrites, catecholamines, and dopamine were measured by enzyme-linked immunosorbent assay (ELISA) and high performance liquid chromatography (HPLC). Arterial blood pressure, cardiac output, oxygen consumption and total peripheral resistance were determined at Baseline, 100W, and peak ergometric stress by standard techniques. There were no apparent differences (p < .05) observed in biochemical markers relating to vascular function and adaptation including, serum nitrates/nitrites, norepinephrine, dopamine, and plasma VEGF. No differences were found relative to cardiac output, stroke volume, cardiopulmonary or myocardial oxygen consumption, expired ventilation, heart rate, arteriovenous oxygen difference, total peripheral resistance, and mean arterial pressure. Due to methodological issues related to the redundant oligonucleotide DNA microarray and real-time PCR gene expression analyses, results of these experiments were uninterpretable. Thus, the research hypothesis was rejected. Conversely, significant (p < .05) differences were observed in waist: hip ratios, recovery: peak systolic blood pressure ratio at 1 minute post-exercise and %VEGFR2 expression. OSA was associated with elevations in both waist: hip ratios and recovery: peak systolic blood pressure ratio at 1 minute post-exercise as well as significant depression of %VEGFR2 profiles. Moreover, significant negative correlations were found regarding waist: hip ratios and %VEGFR2 expression (r = -.69;p =.005) and recovery: peak systolic blood pressure ratio at 1 minute post-exercise and %VEGFR2 expression (r = -.65;p =.01). These findings did not provide evidence that NO-dependent vasoactive mechanisms are suppressed nor did they support the supposition that angiogenic mechanisms are pathologically activated in sleep-disordered breathing.
Ph. D.

The present study examined the neuropsychological relevance of poor sleep in a sample of community dwelling healthy older adults and a clinical sample of patients with untreated obstructive sleep apnea (OSA) between 40 and 90 years of age. The cognitive performance of 67 patients with obstructive sleep apnea (OSA) was compared to those of 46 controls screened for OSA using a portable device called ApneaLinkTM. The current study identified common neuropsychological variables associated with poor sleep quality in general (i.e., as a result of daytime sleepiness) and neuropsychological variables unique to only OSA patients (i.e., manifesting oxygen desaturation at night in addition to daytime sleepiness). Results indicated executive functions were related to hypoxemia and sustained attention was related to sleep fragmentation in the current study. A medical sequelae model and a neuropsychological sequelae model were tested. The neuropsychological sequelae model predicted whether one was a control or an OSA patient 70% accurately based on the predictors (scores on Wisconsin Card Sorting Test perseverance error, vigilance task, WAIS III forward digit span, WAIS III Block Design, phonemic and semantic fluency, and WAIS III backward digit span). The medical sequelae model predicted OSA status 89% accurately based on the predictors (BMI, depression, subjective sleep quality, age, hypertension, diabetes, total mood disturbance, gender, and general health). The current study provides further justification for OSA screening in the general population during middle age and late adulthood especially in those most at risk (i.e., overweight, male, hypertensive, and poor subjective sleep quality).

The focus of this study is the problem of declining trend in obstructive sleep apnea (OSA) patient compliance. Studies reported improved compliance in patients with chronic diseases due to technology-based interventions. However, researchers have not investigated the advantages of technology to improve the compliance of OSA patients in detail. The specific problem was the lack of engagement between patients and healthcare managers, resulting in low compliance within OSA patients. The purpose of this qualitative study was to evaluate how technology-based interventions can improve OSA patient engagement with the healthcare managers resulting in improved compliance with treatment procedures. In this study, the technology acceptance model was used as the instrument in evaluating the information collected through interviews with 20 healthcare managers about their attitudes toward usage, perceived usefulness, and perceived ease of use. The transcribed interviews were open-coded using the RQDA library in R Studio. In general, results from this study indicated that the healthcare managers showed a positive attitude towards the use of technology for patient engagement and expressed that the technology is useful for patient engagement and is easier to use. However, they identified technology-related and patient-related challenges in implementing technology for patient engagement. Further, the respondents identified process-related and patient-related opportunities in using technology for patient engagement. Results from this study have practice and policy implications by enabling healthcare managers to devise better compliance plans for OSA patient management. The findings could have a social benefit by helping healthcare managers to implement technology-based interventions to better achieve a higher compliance resulting in better patient health at lower costs.

Avant leur mise sur le marché, l'évaluation clinique des médicaments repose sur des essais contrôlés randomisés. Bien qu'ils représentent la méthode de référence, leurs résultats sont nécessairement limités aux patients inclus dans ces essais. De plus, ils sont d’abord conçus pour mesurer l'efficacité des traitements, avant d’évaluer leurs effets indésirables. Concernant le syndrome d'apnées du sommeil (SAS), alors que de nombreux essais médicamenteux ont été menés, la plupart des résultats sont de faible niveau de preuve, voire contradictoires. Outre la durée et les effectifs limités de ces essais, une explication est que le SAS est une pathologie hétérogène en termes de symptômes et de physiopathologie, incluant divers "phénotypes" de patients. Des données de vie réelle sont donc nécessaires pour définir quels médicaments pourraient améliorer le SAS ou les comorbidités associées et quels patients pourraient en bénéficier. Au contraire, les cliniciens doivent être avertis que certains médicaments peuvent induire ou aggraver le SAS.La pharmacoépidémiologie fait désormais partie de toute enquête de pharmacovigilance, car elle permet une approche à la fois descriptive et comparative des notifications spontanées. Des associations entre l'exposition à un ou plusieurs médicaments et l'apparition d'effets indésirables peuvent ainsi être recherchées. Comme pour toutes les études observationnelles, la principale difficulté consiste à contrôler les facteurs de confusion. L'un des modèles couramment utilisés est l'analyse cas/non-cas, qui étudie la disproportionnalité entre le nombre d’effets indésirables rapportés avec le médicament d’intérêt, par rapport aux effets notifiés pour les autres médicaments. Nous avons ainsi montré des associations significatives entre l'utilisation de baclofène, des gabapentinoïdes ou de l'acide valproïque et la survenue de SAS dans la base de pharmacovigilance de l'OMS, suggérant le rôle du système GABAergique dans la pathogenèse des apnées centrales d’origine médicamenteuse. Un signal de disproportionnalité a également été observé pour le ticagrélor, reposant sur un mécanisme d'action différent.Les analyses pharmacoépidémiologiques permettent également d'étudier le bénéfice des médicaments en vie réelle. Le score de propension est utilisé pour minimiser les biais de sélection et recréer des conditions de comparabilité proches de celles des essais randomisés. À l'aide de ces méthodes statistiques, nous avons évalué l'intérêt potentiel de cibler le système rénine-angiotensine pour la prise en charge de l'hypertension artérielle chez les patients atteints d’apnées obstructives, en particulier avec l’utilisation des sartans. Chez ces mêmes patients apnéiques et hypertendus, nos travaux suggèrent que les diurétiques pourraient diminuer la sévérité des apnées, notamment en cas de surpoids ou d’obésité modérée. Des études prospectives sont désormais nécessaires afin de confirmer ces résultats, car les données de vie réelle ne peuvent se substituer aux essais cliniques contrôlés
The clinical evaluation of drugs before approval is based on randomized controlled trials. Although they are considered as the gold standard for testing drugs, their results are necessarily limited to patients included in the trials. Moreover, almost all clinical trials are primarily designed to assess the efficacy of a treatment, so safety is only a secondary concern. Regarding sleep apnea syndrome (SAS), while many drug trials have been conducted, most of the results are weak or even contradictory. In addition to limited trial duration and population size, one explanation is that the sleep apnea population is highly heterogeneous with respect to symptoms and physiological traits linked to disease pathogenesis, giving various patient “phenotypes”. Real-life data are therefore needed to define which drugs could improve SAS or associated comorbidities and who might benefit from them. On the contrary, clinicians need to be aware that some drugs may induce or worsen sleep apnea.Pharmacoepidemiology is now part of any pharmacovigilance survey, as it provides both descriptive and comparative approaches of spontaneous reports. Associations between the exposure to one or more drugs and the occurrence of adverse effects can thus be sought. As for all observational studies, the major difficulty is to control for confounding factors. One of the study designs commonly used, is the case/non-case analysis, which investigates disproportionality between the numbers of adverse drug reactions reported with the drug of interest compared to the number reported with all other drugs. In this way, we showed significant associations between the use of baclofen, gabapentinoids or valproic acid and the reporting of SAS in the WHO drug adverse event database, suggesting a role of the GABAergic system in the pathogenesis of drug-induced central sleep apnea. A disproportionality signal was also found for ticagrelor, based on a different mechanism of action.Pharmacoepidemiological analyses also make it possible to study the benefit of drugs in real-life. Propensity scores are used to minimize selection bias, leading to a comparability between the exposure groups close to that observed in randomized trials. Using these statistical methods, we have investigated the potential value of targeting the renin-angiotensin system for the management of hypertension in obstructive sleep apnea (OSA) patients, especially the use of sartans. For hypertensive apneic patients, our work suggests that diuretics could decrease the severity of OSA, particularly in the overweight or moderately obese. Prospective studies are now needed to confirm these findings, because real-life data cannot be a substitute for controlled clinical trials

Background-Previous studies have documented a high prevalence of atrial fibrillation (AF) in individuals with obstructive sleep apnea (OSA). Central sleep apnea (CSA) has been associated with AF in patients with heart failure. However, data from prospective cohorts are sparse and few studies have distinguished the associations of obstructive sleep apnea from CSA with AF in population studies. Methods and Results-We assessed the association of obstructive sleep apnea and CSA with incident AF among 2912 individuals without a history of AF in the SHHS (Sleep Heart Health Study), a prospective, community-based study of existing ("parent") cohort studies designed to evaluate the cardiovascular consequences of sleep disordered breathing. Incident AF was documented by 12-lead ECG or assessed by the parent cohort. obstructive sleep apnea was defined by the obstructive apnea-hypopnea index (OAHI). CSA was defined by a central apnea index >= 5 or the presence of Cheyne Stokes Respiration. Logistic regression was used to assess the association between sleep disordered breathing and incident AF. Over a mean of 5.3 years of follow-up, 338 cases of incident AF were observed. CSA was a predictor of incident AF in all adjusted models and was associated with 2-to 3-fold increased odds of developing AF (central apnea index >= 5 odds ratio [OR], 3.00, 1.40-6.44; Cheyne-Stokes respiration OR, 1.83, 0.95-3.54; CSA or Cheyne-Stokes respiration OR, 2.00, 1.16-3.44). In contrast, OAHI was not associated with incident AF (OAHI per 5 unit increase OR, 0.97, 0.91-1.03; OAHI 5 to <15 OR, 0.84, 0.59-1.17; OAHI 15 to <30 OR, 0.93, 0.60-1.45; OAHI >= 30 OR, 0.76, 0.42-1.36). Conclusions-In a prospective, community-based cohort, CSA was associated with incident AF, even after adjustment for cardiovascular risk factors.

La síndrome d'apnees-hipopnees de la son (SAHS) s'ha associat a la presència d'hipertensió arterial (HTA), especialment amb la hipertensió resistent (HR). A més, s'ha descrit que el tractament del SAHS amb pressió positiva contínua en la via aèria (CPAP) aconsegueix reduccions en la pressió arterial (PA), però, hi ha una gran variabilitat en la resposta observada i no hi ha evidència a llarg termini. Per tant, els quatre estudis que composen la present tesi doctoral tenen com a objectiu contribuir al coneixement sobre la relació entre ambdues patologies, i establir l'efecte del tractament del SAHS sobre la PA en diferents fenotips de PA. En aquest sentit, es va desenvolupar i implementar un estudi prospectiu per avaluar l'impacte del SAHS i el seu tractament en el pronòstic cardiovascular en pacients amb HR. En el segon estudi, es va avaluar la prevalença de SAHS en subjectes amb HR, així com l'impacte d'aquesta patologia sobre el control de la PA, observant-se una prevalença de SAHS del 83.5%, i una associació dosi-resposta entre la gravetat del SAHS i els valors de la PA, especialment de la PA nocturna. En el tercer estudi, es va avaluar l'efecte de la CPAP en subjectes normotensos. Els resultats mostren que el patró circadià de la PA o la presència d'hipertensió emmascarada tenen un paper important en l'efecte de la CPAP sobre la PA, sent els pacients amb un patró circadià non-dipper i aquells amb hipertensió emmascarada els que més es beneficien del tractament amb CPAP, en termes de reducció de la PA. A més, en pacients normotensos amb patró circadià dipper, el tractament amb CPAP podria incrementar la PA nocturna, per tant aquests resultats mostren la necessitat de dur a terme un monitoratge de la PA prèviament a la prescripció de CPAP per tal de definir subgrups de resposta al tractament. Finalment, i de continuïtat amb aquest estudi, es va avaluar l'efecte del tractament amb CPAP en pacients amb HTA segons el patró circadià basal, i els resultats mostren de nou, que només els pacients amb tractament amb CPAP i un patró circadià non-dipper redueixen els valors de PA. En definitiva, els resultats exposats en la present tesi doctoral són de rellevància i interès en la pràctica clínica habitual donat que poden ajudar a millorar el maneig i indicació del tractament amb CPAP en pacients amb SAHS i contribuir a establir una indicació més individualitzada i cost-efectiva.
El síndrome de apneas-hipopneas del sueño (SAHS) se ha asociado a la presencia de hipertensión arterial (HTA), especialmente con la hipertensión resistente (HR). Además, se ha descrito que el tratamiento del SAHS con presión positiva continua en la vía aérea (CPAP) consigue reducciones en la presión arterial (PA), pero existe una gran variabilidad en la respuesta observada y no hay evidencia a largo plazo. Por lo tanto, los cuatro estudios de esta tesis tienen cómo objetivo contribuir al conocimiento sobre la relación de ambas patologías, y establecer el efecto del tratamiento del SAHS sobre la PA en distintos fenotipos de PA. En este sentido, se desarrolló e implementó un estudio prospectivo para evaluar el impacto del SAHS y su tratamiento en el pronóstico cardiovascular en pacientes con HR. En el segundo estudio, se evaluó la prevalencia de SAHS en sujetos con HR, así cómo el impacto de esta patología sobre el control de la PA, observándose una prevalencia de SAHS del 83.5%, además de, una asociación dosis-respuesta entre la gravedad del SAHS y los valores de la PA, especialmente la PA nocturna. En el tercer estudio, se evaluó el efecto de la CPAP en sujetos normotensos. Los resultados muestran que el patrón circadiano de la PA o la presencia de hipertensión enmascarada tiene un papel importante en el efecto de la CPAP sobre la PA, siendo los sujetos con patrón circadiano non-dipper y aquellos con hipertensión enmascarada los que más se benefician del tratamiento con CPAP, en términos de reducción de la PA. Además, en pacientes normotensos con patrón circadiano dipper, el tratamiento con CPAP podría incrementar la PA nocturna, por lo que estos resultados muestran la necesidad de llevar a cabo una monitorización de la PA previamente a la prescripción de CPAP con el fin de definir subgrupos de respuesta al tratamiento. Finalmente, y de continuidad con este estudio, se evaluó el efecto del tratamiento con CPAP en pacientes con HTA según el patrón circadiano basal, y los resultados muestran de nuevo que sólo los pacientes en tratamiento con CPAP y con un patrón circadiano non-dipper reducen los valores de PA. En definitiva, los resultados expuestos en la presente tesis doctoral son de relevancia e interés en la práctica clínica habitual dado que pueden ayudar a mejorar el manejo e indicación del tratamiento con CPAP en pacientes con SAHS y contribuir a establecer una indicación más individualizada y coste-efectiva.
Obstructive sleep apnea syndrome (OSAs) has been associated with arterial hypertension (HTN), especially with resistant hypertension (RH). In addition, it has been described that the treatment of OSAs with continuous positive airway pressure (CPAP) produces reductions in blood pressure (BP), nevertheless there is a great variability in the BP response and there is no evidence at long-term. Despite the relation between both pathologies, some aspects remain unclear due to the limited available evidence and the controversy in the published studies. Therefore, the four studies that shape this doctoral thesis aim to contribute to the knowledge about the relation between both pathologies, and to determine the effect of CPAP treatment on BP in different BP phenotypes. In this sense, a prospective study was carried out and implemented to evaluate the impact of OSAs and its treatment on cardiovascular prognosis in patients with RH. In the second study, we evaluate the prevalence of OSAs and its impact on BP in subjects with RH, and a prevalence of 83.5% was found. Moreover, we found a dose-response association between OSAs’ severity and BP values, especially with nocturnal BP. In the third study, the effect of CPAP on normotensive subjects was evaluated. The results show that the circadian BP pattern or the presence of masked hypertension could determine the effect of CPAP on BP. It was observed that patients with a non-dipper circadian pattern and those with masked hypertension benefited the most from CPAP treatment, in terms of BP reduction. Moreover, an increase in nocturnal BP with CPAP treatment was observed in normotensive subjects with a dipper circadian pattern. These results show the necessity to perform a BP monitoring prior to CPAP prescription in order to define subgroups of treatment response. Finally, we evaluated if there is a differential effect of CPAP treatment on BP in patients with HTN according to the baseline circadian BP pattern. The results of this study showed again that only patients with CPAP treatment and non-dipper circadian pattern reduce BP. In conclusion, the results presented in this doctoral thesis could be of relevance and interest in the clinical practice because they can help to improve the management and indication of CPAP treatment in patients with OSAs and contribute to establishing a more individualized and cost-effective indication of the CPAP treatment.

El síndrome del párpado laxo (SPL) y el glaucoma son las patologías oculares más frecuentemente asociadas al síndrome de apnea-hipopnea del sueño (SAHS), que se han evaluado en cuatro estudios. En el primer estudio, la prevalencia de SPL entre pacientes con SAHS fue del 16% y la prevalencia de SAHS entre pacientes con SPL fue del 85%, de los cuales, el 65% tenían SAHS severo. Los pacientes con SAHS presentaron mayor hiperlaxitud palpebral. En el segundo estudio, la prevalencia de glaucoma entre los pacientes con SAHS pero sin SPL fue del 5.3%, mientras que entre los pacientes con SAHS y con SPL, alcanzó el 23%. En el tercer estudio, los pacientes con SPL presentaron una histéresis corneal significativamante más baja. En el cuarto estudio, los pacientes con SPL presentaron unos cambios significativos en el epitelio conjuntival caracterizados por aumento de la metaplasia escamosa y disminución de las células caliciformes.
Floppy eyelid syndrome (FES) and glaucoma are the most common ocular disorder associated with obstructive sleep apnea (OSA) and it has been done four studies. The results of the first study showed a prevalence of FES in OSA patients of 16% and a prevalence of OSA in FES patients of 85%, in those 65% had severe OSA. Patients with OSA had a significantly higher incidence of eyelid hyperlaxity. The second study showed that the prevalence of glaucoma in OSA patients without FES was 5.3%, and the prevalence of glaucoma in patients with OSA and with FES raised 23%. The results of the third study showed that patients with FES had statistically lower corneal hysteresis values. In the last study, patients with FES were more likely to exhibit abnormal conjunctival cytology characterized by an increase in squamous metaplasia and a decrease in the number of goblet cells.
La síndrome de la parpella laxa (SPL) i el glaucoma són les patologies oculars més freqüentment associades a la síndrome de l’apnea-hipopnea del son (SAHS), que s’han evaluat en quatre estudis. En el primer estudi, la prevalença de SPL entre pacients amb SAHS fou del 16% i la prevalença de SAHS entre pacients amb SAHS i amb SPL fou del 85%, dels quals, el 65% tenien SAHS sever. Els pacients amb SAHS van presentar major hiperlaxitud palpebral. En el segon estudi, la prevalença de glaucoma entre pacients amb SAHS però sense SPL fou del 5.3%, mentre que entre pacients amb SAHS i SPL, va arribar al 23%. En el tercer estudi, el pacients amb SPL van presentar una histèresis corneal significativament més baixa. En el quart estudi, els pacients amb SPL presentaren canvis significatius en l’epiteli conjuntival caracteritzats per augment de la metaplasia escamosa i disminució de les cèl.lules caliciformes.

Patients with Cushing’s syndrome often complain about sleep disruption and excessive day time sleepiness, which could contribute to worsening quality of life and metabolic comorbidities (obesity, hypertension, diabetes mellitus, dyslipidaemia) associated with hypercortisolism. Sleep disorders have been shown to increase the risk of developing cardiovascular disease and that the risk of cardiovascular disease in patients with hypercortisolism may be worsened by impaired sleep. Cushing’s syndrome patients may also be at increased risk for obstructive sleep apnea due to their obesity.
Dissertation (MSc)--University of Pretoria, 2020.
Physiology
MSc
Restricted

Dissertação de Mestrado em Biotecnologia Farmacêutica apresentada à Faculdade de Farmácia
A Síndrome Apneia Obstrutiva do Sono (SAOS) é reconhecida como uma das mais comunsperturbações do sono. Esta doença é caracterizada por episódios regulares de obstrução, parcialou completa, das vias aéreas superiores durante o sono. Estima-se que 80 a 90 % dos casos deSAOS não estejam diagnosticados, fundamentalmente devido ao diagnóstico tardio e baixoconhecimento da doença. A SAOS não tratada está associada a uma maior predisposição a váriosproblemas de saúde, bem como a uma maior mortalidade. Além disso, vários estudos demonstramuma associação entre a SAOS e comprometimento cognitivo e demência, que são frequentementeassociados ao envelhecimento. Neste caso, estas alterações são observadas em doentes comSAOS em idades precoces. Evidências sugerem que a SAOS pode promover/agravar oenvelhecimento através da indução de mecanismos celulares e moleculares associados a este.Neste contexto, os objetivos principais deste trabalho são:1) investigar se os doentes com SAOS apresentam alterações celulares e/ou molecularesperiféricas associadas ao envelhecimento; 2) avaliar se o tratamento da SAOS atenua essasalterações; 3) sensibilizar a população para os fatores de risco, consequências e falta dediagnóstico da SAOS.Uma coorte de 6 doentes Portugueses do sexo masculino [idade: 53 ± 4 anos; IMC: 32,1 ± 2,5]com diagnóstico de SAOS severa [60.9±12 apneias/hipopneia por hora – AHI] foramacompanhados desde o momento do diagnóstico com polissonografia – PSG (t0), após 4 meses(t4M) e 2 anos (t24M) de tratamento com o tratamento de referência – CPAP. Em cada fase doestudo (t0, t4M and t24M) foram realizadas colheitas de sangue aos doentes e controlos e isoladascélulas mononucleares do sangue periférico (PBMCs). Foram avaliadas características doenvelhecimento celular e molecular, nomeadamente a instabilidade genómica, a perda daproteostase e o encurtamento dos telómeros. Todos os resultados foram comparados comcontrolos de idades correspondentes [idade: 47 ± 7 anos: IMC: 25,6 ± 0,5; AHI: 4,7 ± 0,8] e comcontrolos jovens [idade: 24 ± 2 anos; IMC: 23,5 ± 2,8].Os resultados demonstram que em doentes com SAOS se verificam alterações ao nível dahomeostasia proteica, instabilidade genómica e encurtamento dos telómeros. O tratamento decurta duração não parecem ser suficientes para reverter as consequências da SAOS, enquantoque o tratamento a longo-termo com CPAP pode parcialmente restabelecer algumas dasalterações.Em suma, este trabalho sugere que a SAOS promove/agrava o envelhecimento e as doençasassociadas a este. Mais estudos são necessários que permitam descobrir novos biomarcadoresque permitam o diagnóstico precoce da SAOS, estratificação dos doentes e a monitorização daresposta ao tratamento. Por fim, o diagnóstico e tratamento numa fase precoce da SAOS podemconstituir uma nova estratégia para atenuar o envelhecimento.
Obstructive Sleep Apnea (OSA) has been recognized as one of the most common sleep disorders.OSA is characterized by regular episodes of complete or partial obstruction of the upper airwaysduring sleep. Nevertheless, it is estimated that 80 to 90 % of the OSA cases are undiagnosedmainly due to late diagnosis and lack of disease awareness. Untreated, OSA has been associatedwith an increased predisposition to several health problems and increased mortality. Moreover,there is sizable evidence showing the association of OSA with mild cognitive impairment anddementia, which are commonly associated with aging, but this alteration appear at younger agesin OSA patients. There are evidences that OSA might promote/aggravate aging by inducingcellular and molecular aging mechanisms. In this context, the main objectives of present work are:1) to investigate whether OSA patients show peripheral aging-related cellular and molecularimpairments; 2) to assess if OSA treatment can ameliorate such alterations; 3) to raise awarenessof the population to alert the risk factors, consequences and lack of diagnosis of OSA.A cohort of 6 Portuguese male patients [age: 53 ± 4 years; BMI: 32.1 ± 2.5] diagnosed with severeOSA [60.9 ± 12 apneas/hypopneas per hour - AHI] was followed from the moment of diagnosiswith polysomnography - PSG (t0), up to 4 months (t4M) and 2 years (t24M) of treatment withstandard treatment - CPAP. In each phase (t0, t4M and t24M), blood was collected from patients andcontrols subjects and peripheral blood mononuclear cells were isolated. Hallmarks of cellular andmolecular aging were evaluated, namely, genomic instability, loss of proteostasis and telomereshortening. All results were compared to age-matched controls [age: 47±7 years; BMI: 25.6 ± 0.5;AHI: 4.7 ± 0.8] and with younger controls [age: 24 ± 2 years; BMI: 23.5 ± 2.8].The results showed that OSA patients induce impairments in protein homeostasis, nucleargenomic instability and telomere shortening. Short-term treatment does not seem enough torecover from OSA consequences while long-term CPAP treatment might partially re-stablishsome alterations.Overall, this work suggests that OSA promotes/aggravates aging and aging-related diseases.Further investigations are needed to find new biomarkers allowing for OSA early diagnosis, patientstratification and treatment response monitoring. In the end, OSA early diagnosis and treatmentmay constitute a new strategy to delay ageing.

碩士
國立臺北護理健康大學
運動保健研究所
102
Obstructive sleep apnea (OSA) is a common sleep disorder that results in symptoms of excessive daytime sleepiness, memory deterioration, and attention deficiency causing negative effects on the quality of life. Primary treatment includes continuous positive airway pressure (CPAP) and oral appliances. However, due to the discomfort of device installation and financial burden, patients lack tolerance on using appliances. The purpose of this study was to explore the effects of expiratory muscle strength training (EMST) intervention on apnea-hypopnea index (AHI), respiratory muscles strength, daytime sleepiness and sleep quality in obstructive sleep apnea patients. The subjects were 25 OSA patient diagnosed in sleep center randomly assigned to experimental and control groups. All participants were given the test of Polysomnography (PSG), maximum expiratory pressure (PEmax), Epworth Sleepiness Scale (ESS) and Pittsburgh sleep quality index (PSQI) before and after training course. The experimental and control groups were both given 5 weeks of EMST, 5 days a week, every day 25 times breaths; experimental group received 75%PEmax training pressure and control group 0%PEmax training pressure. The measured data analyzed by Mann-Whitney U test. The results showed that after 5 weeks of expiratory muscle strength training, in mild OSA group the AHI and ESS were significantly reduced than control group (p < .05) and PEmax was greater than control group (p < .05). Besides, in moderate OSA group PSQI was significantly redused than control group (p < .05) and PEmax was greater than control group (p < .05). In conclusion, 5 weeks of expiratory muscle strength training can improve AHI, daytime sleepiness and expiratory muscle strength in mild OSA.

碩士
高雄醫學大學
醫學系神經學科碩士班
103
Obstructive sleep apnea (OSA) is a common sleep disorder characterized by chronic intermittent hypoxia and sleep fragmentation. Patients with OSA often complain poor attention, impaired vigilance and cognitive decline. Using comprehensive Frontal Test Battery, Flanker task and event-related potentials (P300, error-related negativity (ERN) and error positivity (Pe)), the aims of this study are 1) to evaluate the cognitive deficit, particularly action monitoring, 2) to investigate the effect of OSA on P300, ERN and Pe, and 3) to clarify the possible mechanism of cognitive dysfunction in patients with OSA syndrome. 25 OSA patients, based on polysomnography (PSG) (male: 19, mean age: 49.7 ± 8.6 years) and 12 normal controls (male: 6, mean age: 43.9 ± 8.7 years) underwent comprehensive Frontal Test Battery, Flanker task and event-related potentials assessments (P300, error-related negativity and error positivity). In comparison with controls, the OSA patients showed significant impairment in global cognition, attention and high executive function. Besides, the OSA patients have lower correct rate and lower error correcting rate in Flanker task. The OSA patients also have significant prolonged P300 and ERN latencies. Furthermore, the arousal index was significantly correlated with attention and performance of Flanker task. The oxygen desaturation index was significantly correlated with attention. The duration and severe of nocturnal hypoxia was significantly correlated with amplitude of ERN. We conclude that the OSA patients may manifest with significant frontal dysfunction, mainly on attention, executive function and action monitoring. We suggest that the attentional impairment might be due to sleep fragmentation and intermittent hypoxia, and the impairment of action monitoring might be due to sleep fragmentation and severity of nocturnal hypoxia.